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  • The hippocampus is the primary brain structure

    2023-12-08

    The hippocampus is the primary brain structure involved in learning and memory. The role of hippocampal synaptic plasticity in neurological processes in cognition and depression has been extensively demonstrated. Synaptophysin is a critical substance in synaptogenesis, which is necessary for learning and memory. Nociceptive sensitization in mice with complex regional pain syndrome (CRPS) is accompanied by working memory dysfunction in the novel object recognition test and social interaction test. Furthermore, structural changes in the brain were accompanied by the down-regulation of synaptophysin [42]. Administration of lithium (Li) exerts neurotrophic effects by promoting dendritic outgrowth, resulting in enhanced levels of synaptophysin [43]. PSD-95 is a major scaffolding protein in synaptic plasticity and is also significantly down-regulated in the brains of CUMS-treated rats; the decrease in PSD-95 is positively correlated with depressive symptoms [44]. PSD-95 knockout mice exhibited a deficit in spatial learning [45]. In a cognitive impairment model induced by injection of amyloid-β (Aβ1–42) bilaterally into the hippocampus of rats, neuronal degeneration and apoptosis in the hippocampus was accompanied by down-regulation of PSD-95 [46]. In addition to synaptophysin and PSD-95, growing evidence suggests BDNF also plays an important role in cognition and the pathogenesis of depression. As a member of the neurotrophin family, BDNF is involved in neuronal proliferation and differentiation. BDNF was down-regulated in the blood of patients with Major Depressive Disorder, which was reversed by antidepressant therapy [21], [35], [47], [48].
    Conclusion
    Introduction 5-Lipoxygenase (5-LOX) is a key enzyme in the metabolism of arachidonic MK-4827 (AA) to produce leukotrienes. It catalyzes the two-step conversion from AA to leukotriene A4 (LTA4). LTA4 is further metabolized by leukotriene A4 hydrolase to leukotriene B4, or by leukotriene C4 synthase to leukotriene C4 and then to leukotriene D4 and E4. Leukotrienes are important mediators of inflammatory and allergic diseases, and also play roles in cardiovascular diseases and cancers.3, 4, 5, 6 The upstream enzyme of leukotrienes, 5-LOX, has been validated as a drug target for inflammation and related disorders therapy. Several types of 5-LOX inhibitors have been reported, including redox, iron ligand, nonredox, and competitive inhibitors (for review see Ref. 8). Up to now, only one 5-LOX inhibitor, zileuton, entered the market. However, weak potency and short duration are the therapeutic problems of zileuton. Development of safe and effective 5-LOX inhibitors is highly demanded. We previously reported a model for the active conformation of human 5-LOX and new inhibitors identified by virtual screening using this model. Among these inhibitors, naphthalen-1-yl 3,5-dinitrobenzoate (JMC-4), shows activity in the micromolar range and possesses novel structure compared to known 5-LOX inhibitors. Through analyzing of the docking conformation of JMC-4 with 5-LOX, we recognized several key interactions between the compound and the enzyme. As shown in Figure 1, one nitro group makes a hydrogen bond with His600 of 5-LOX; the naphthyl group is crucial to form hydrophobic interaction with the pocket around Leu414. The ester linker of JMC-4 is close to Tyr181 and Gln363, but no hydrogen bond is formed for the relative position. Guided by this interaction model, in the present work, we tried to improve the potency of JMC-4. Firstly, phenyls with different substituent groups were introduced to search a more active hydrophobic moiety. Secondly, amide bond was used to replace the ester bond to test a linker with hydrogen bond donor. Finally, as the binding conformation shows only one nitro group makes a key interaction with the target, the mono-nitro group counterpart of JMC-4 and the compounds with carboxyl group instead of nitro group were tested.
    Results and discussion